Obesity: Sjöstrand M

Sjöstrand M, Eriksson JW. · The Lundberg Laboratory for Diabetes Research, Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden. · Mol Cell Endocrinol. · Pubmed #18599191 No free full text.

Abstract: Dysregulated hormonal, metabolic and neural signalling within and between organs can contribute to development of metabolic diseases including type 2 diabetes. Insulin-antagonistic effects of hormones, cytokines and excess metabolic substrates such as glucose and fatty acids may be exerted via common mechanisms involving for example reactive oxygen species (ROS) accumulation and associated inflammatory responses. Visceral adiposity is a central component of the metabolic syndrome and it is also strongly associated with insulin resistance. Both visceral obesity and insulin resistance are important risk factors for the development of type 2 diabetes. In the development of insulin resistance, it is likely that intra-abdominal adipose tissue plays a critical role in a complex endocrine and neural network involving several tissues. This review paper focuses on neuroendocrine 'stress' factors that target insulin-responsive tissues, in particular adipose tissue. We propose that there are common pathways by which dysregulation in different endocrine systems may contribute to the development of type 2 diabetes.

Murdolo G, Sjöstrand M, Strindberg L, Gudbjörnsdóttir S, Lind L, Lönnroth P, Jansson PA. · Department of Internal Medicine, Section of Internal Medicine, Endocrine and Metabolic Sciences, Perugia University, Via Enrico Dal Pozzo I, Perugia, Italy. · J Clin Endocrinol Metab. · Pubmed #18460559 links to  free full text

Abstract: CONTEXT: Impairment of insulin-mediated capillary recruitment in skeletal muscle contributes to a hampered glucose uptake in obesity. OBJECTIVE: The objective of this study was to evaluate whether metacholine (MCh), a nitric oxide vasodilator, potentiates muscle capillary recruitment and forearm glucose uptake (FGU) during physiological hyperinsulinemia. DESIGN: The double-forearm technique [i.e. infused vs. control (Ctrl) forearm] was combined with im microdialysis during an oral glucose tolerance test in 15 nondiabetic, obese subjects divided into a group of insulin-resistant (IR) (n = 7) and insulin-sensitive (n = 8) individuals. RESULTS: After the oral glucose tolerance test, forearm blood flow in the Ctrl forearm was unchanged, whereas it increased about 3-fold (P < 0.0001 vs. baseline) in response to MCh. Capillary permeability surface area product for glucose (PS(glu)) (capillary recruitment), FGU, and interstitial insulin concentrations increased significantly over time (P < 0.001) in both forearms. Compared with insulin-sensitive, the IR subjects exhibited lower PS(glu) (P < 0.001) and FGU (P < 0.01) in the Ctrl arm, whereas this difference was insignificant in the MCh arm despite the blunted forearm blood flow increase. Moreover, in IR individuals MCh significantly (P < 0.05) ameliorated the delayed onset of insulin action, i.e. the FGU response to hyperinsulinemia. Finally, we found PS(glu) to be a strong and independent predictor of FGU response (adjusted R(2) 0.72; P < 0.0001). CONCLUSIONS: MCh-induced vasodilation may improve the microvascular and metabolic responses to physiological hyperinsulinemia in obese, IR individuals. Further studies are required to unravel whether stimulation of nitric oxide production in skeletal muscle may represent an attractive therapeutic approach to bypassing cellular resistance to glucose disposal.

Sjöstrand M, Gudbjörnsdottir S, Holmäng A, Lönn L, Strindberg L, Lönnroth P. · Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, Göteborg, Sweden. · Diabetes. · Pubmed #12196467 links to  free full text

Abstract: Insulin-resistant subjects have a slow onset of insulin action, and the underlying mechanism has not been determined. To evaluate whether a delayed transcapillary transport is part of the peripheral insulin resistance, we followed the kinetics of infused insulin and inulin in plasma and muscle interstitial fluid in obese insulin-resistant patients and control subjects. A total of 10 lean and 10 obese men (BMI 24 +/- 0.8 vs. 32 +/- 0.8 kg/m(2), P < 0.001) was evaluated during a hyperinsulinemic-euglycemic clamp (insulin infusion rate 120 mU. m(-2). min(-1)) combined with an inulin infusion. Measurements of insulin and inulin in plasma were taken by means of arterial-venous catheterization of the forearm and microdialysis in brachioradialis muscle combined with forearm blood flow measurements with vein occlusion pletysmography. The obese subjects had a significantly lower steady-state glucose infusion rate and, moreover, demonstrated a delayed appearance of insulin (time to achieve half-maximal concentration [T(1/2)] 72 +/- 6 vs. 46 +/- 6 min in control subjects, P < 0.05) as well as inulin (T(1/2) 83 +/- 3 vs. 53 +/- 7 min, P < 0.01) in the interstitial fluid. Also, the obese subjects had a delayed onset of insulin action (T(1/2) 70 +/- 9 vs. 45 +/- 5 min in control subjects, P < 0.05), and their forearm blood flow rate was significantly lower. These results demonstrate a delayed transcapillary transport of insulin and inulin from plasma to the muscle interstitial fluid and a delayed onset of insulin action in insulin-resistant obese subjects.

Sjöstrand M, Gudbjörnsdottir S, Holmäng A, Strindberg L, Ekberg K, Lönnroth P. · Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, Göteborg S-413 45, Sweden. · J Clin Endocrinol Metab. · Pubmed #11994365 links to  free full text

Abstract: The aim of this project was to study the regulation of interstitial glycerol levels in muscle in normal subjects, and to estimate interstitial muscle glycerol in obese subjects and patients with type 2 diabetes. In healthy lean subjects, microdialysis of forearm sc and muscle tissue were combined with arterial and deep venous catheterization, as well as blood flow registrations during oral glucose ingestion. In two other separate studies, obese (n = 9) vs. lean (n = 10) subjects and type 2 diabetes patients (n = 8) vs. weight-matched control subjects (n = 8) were investigated by means of muscle microdialysis during a euglycemic hyperinsulinemic clamp. Oral glucose ingestion suppressed the interstitial sc glycerol concentration by approximately 40% (P < 0.05), whereas no significant reduction of muscle interstitial glycerol was found. In contrast to the significant muscle interstitial-arterial (I-A) glycerol difference, the venous-arterial difference was small and varying throughout the oral glucose tolerance test. At steady-state hyperinsulinemia, obese subjects' interstitial muscle glycerol and I-A glycerol difference were both significantly higher than lean controls, whereas type 2 diabetes patient had interstitial muscle glycerol concentrations and I-A glycerol differences similar to those found in weight-matched controls. A significant and marked I-A glycerol difference exists in the absence of a significant venous-arterial difference, indicating that muscle glycerol cannot be taken as a marker of intramyocellular lipolysis because local turnover of muscle glycerol might be significant. The present data also suggest that, in contrast to sc tissue, muscle tissue lacks a clear antilipolytic effect of insulin. Moreover, the muscle interstitial glycerol concentration is elevated in obese patients but does not precipitate insulin resistance and type 2 diabetes.

Sjöstrand M, Gudbjörnsdottir S, Strindberg L, Lönnroth P. · Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, S-41345 Göteborg, Sweden. · Diabetes. · Pubmed #15616023 links to  free full text

Abstract: Obese subjects exhibit a delay in insulin action and delivery of insulin to muscle interstitial fluid during glucose/insulin infusion. The aim of the present study was to follow the distribution of insulin to skeletal muscle after an oral glucose load in obese subjects. We conducted an oral glucose tolerance test (OGTT) in 10 lean and 10 obese subjects (BMI 23 +/- 0.6 vs. 33 +/- 1.2 kg/m(2); P < 0.001). Insulin measurements in muscle interstitial fluid were combined with forearm arteriovenous catheterization and blood flow measurements. In the obese group, interstitial insulin was significantly (35-55%) lower than plasma insulin (P < 0.05) during the 1st h after the OGTT, whereas in lean subjects, no significant difference was found between interstitial and plasma insulin levels during the same time period. The permeability surface area product for glucose, representing capillary recruitment, increased in the lean group (P < 0.05) but not in the obese group (NS). Obese subjects had a significantly higher plasma insulin level at 90-120 min after oral glucose (398 +/- 57 vs. 224 +/- 37 pmol/l in control subjects; P < 0.05). The significant gradient between plasma insulin and muscle interstitial insulin during the first hour after OGTT suggests a slow delivery of insulin in obese subjects. The hindered transcapillary transport of insulin may be attributable to a defect in insulin-mediated capillary recruitment.